Severe Spontaneous Hematomas in Patients Hospitalized with COVID-19

Objective To describe the epidemiological, clinical, laboratory, and radiological characteristics, medical treatment, and outcomes of a case series of severe spontaneous hematoma in COVID-19. Material and Methods. This retrospective study included patients hospitalized for COVID-19 who were diagnosed with severe spontaneous bleeding complications by following a standardized treatment protocol that included computed tomography angiography (CTA) from 1 March 2020 to 28 February 2022. The main outcomes were embolization and all-cause mortality. Baseline variables were analyzed for their association with mortality using bivariable logistic regression, and results were expressed as odds ratios (OR) and 95% confidence intervals (CI). Results In total, 2450 adults were hospitalized for COVID-19 in our center during the study period. 20 patients presented severe and spontaneous intramuscular bleeding (8.1 per 1000 COVID-19 admission vs. 0.47 per 1000 non-COVID-19 admissions, p < 0.001); their median age was 68.5 years (interquartile range (IQR) 63, 80), they had high comorbidity (median Charlson comorbidity index 4.5), and 95% were receiving high doses of heparin. The median interval from COVID-19 symptoms to bleeding was 17 days (IQR 13, 24), and 70% reported cough as a previous symptom. Hypovolemic shock, hypotension, and abdominal pain were the most frequent symptoms of the hematoma. All presented decreased hemoglobin, and 95% required transfusion. Intramuscular hematoma occurred most frequently in the rectus sheath, iliopsoas compartment, and femoral-iliac compartment. All patients underwent embolization; mortality was 45%. We did not identify risk factors associated with an increased risk of death. Conclusion Although severe bleeding is an uncommon complication of COVID-19, its prevalence is higher than in inpatients without COVID-19, it usually needs embolization, and it is associated with high mortality.


Introduction
SARS-CoV-2 infection initially causes a hemostatic disorder with a hypercoagulable state, mainly in severe cases [1], suggesting the need for enhanced thromboprophylactic strategies that have been included in most treatment protocols since the beginning of the pandemic [2]. As infammation starts to improve after the second week, fbrinogen and D-dimer levels decrease, which may increase bleeding risk through an unknown mechanism [3,4]. Tis, combined with other risk factors for bleeding, such as cough or kidney failure, could lead to an increased incidence of hematomas in COVID-19 inpatients [4][5][6].
Te severity of hematomas can be suspected clinically, but confrmation requires computed CTA [5][6][7]. Tis procedure sheds light on the size, location, extension, and artery responsible for the bleeding and assesses the need for treatment, also in cases of active bleeding as low as 0.3 mL/min [5][6][7][8][9][10][11][12], excluding other acute abdominal diseases and being considered the gold standard for the identifcation of spontaneous intramuscular hematomas over other imaging techniques [12].
Te primary aim of this study is to describe incidence, clinical characteristics, and main outcomes in hospitalized COVID-19 patients with severe spontaneous hematomas diagnosed by CTA. Te secondary aim is to identify factors associated with mortality.

Study Design and Setting.
A single-center retrospective study in COVID-19 patients with severe spontaneous hematomas was performed at the Alicante General University Hospital (Spain), a tertiary care institution.
Inclusion criteria were as follows: adults (≥18 years); hospitalized for community or nosocomial SARS-CoV-2 infection from 1 March 2020 to 28 February 2022; developed major spontaneous bleeding in a critical organ; with a decrease in hemoglobin of ≥2 g/dL, a requirement for ≥2 units of packed red blood cells, or presenting hypotension, hemorrhagic shock, or death [13]; and diagnosed using CTA.

Explanatory Variables.
Electronic medical records were reviewed to collect data on demographics, clinical variables (presence of acute abdominal pain or distension), intensive care unit (ICU) admission, surgical or endovascular intervention notes, and the interval between admission and imaging. Laboratory data within 3 days prior to the CTA were considered, including D-dimers, hemoglobin, fbrinogen, partial thromboplastin time, and prothrombin time. A high dose of heparin was defned as over 1 mg/kg enoxaparin every 12 h or equivalent by glomerular fltrate, whereas an intermediate dose was defned as 1 mg/kg enoxaparin every 24 h. In case another low molecular heparin was used, its equivalence with enoxaparin was calculated for an easier comparation.

Outcome Variables.
We evaluated diferences in the incidence of CTA-diagnosed bleeding disorders in inpatients with versus without COVID-19 during the study period. Te main outcomes were the need for embolization or blood transfusion and in-hospital all-cause mortality.

Image Acquisition and Analysis.
All scans were performed on a 128-slice multidetector CT scanner (SOMA-TOM Defnition Edge, Siemens, Germany), with acquisition of noncontrast images followed by acquisition during the arterial and portal venous phases. Bolus tracking was used to optimize the acquisition phase (enhancement threshold of 150 Hounsfeld units). CTA detected active bleeding in all cases, showing hematoma volume and clinical severity.
Two abdominal radiologists with 10 and 15 years of experience retrospectively interpreted all CTA or computed tomography venography studies of the abdomen and pelvis in a clinical setting, assessing the site and extent of hemorrhage and the presence of active contrast extravasation.

Statistical Analysis.
A descriptive statistical analysis was conducted, with categorical variables presented as counts and percentages and continuous variables as median and IQR. Te incidence of bleeding in patients with versus without COVID-19 was compared using the chi-squared test. Baseline variables were analyzed by bivariable logistic regression to test the association with a fatal outcome, with results expressed as OR and 95% CI. Finally, a logistic regression analysis was undertaken to evaluate the association between length of hospital and ICU stay and death outcome. All analyses were performed using SPSS v25.

Ethical Aspects.
Te institutional review board approved the study. As it was retrospective, the requirement for informed consent from participants was waived (EXP. 200145). Te research was conducted according to the principles of the Declaration of Helsinki.
12 patients (60%) required ICU admission, and 8 were treated in the medical ward. Demographic, clinical, laboratory, and radiological fndings, treatment, and outcome in the 20 hospitalized COVID-19 patients are shown in Table 1.

Use of Anticoagulation and Indications.
All patients with hematoma were under treatment with heparin during hospitalization, and all but 1 of these received high doses. Te main indications for anticoagulants were confrmed (n � 5, 24%) or probable pulmonary embolism (n � 4, 20%) and atrial fbrillation (n � 8, 40%).

Outcomes.
Tere were 20 cases of CTA-diagnosed bleeding disorders associated with COVID-19, for an incidence of 8.1 per 1000 admissions. During the same period, 8500 adults without COVID-19 were admitted; 4 were diagnosed with bleeding disorders via CTA (0.47 per 1000 admissions; p < 0.001).
Finally, 9 patients (45%) died; the cause of death was indirectly related to the hemorrhagic complication in 5 (24%) and directly related in 4 (20%). Te bivariable logistic regression analysis did not show evidence that any risk factors (epidemiological data, comorbidities, clinical, laboratory, and treatment) were associated with a fatal outcome among those with hemorrhagic bleeding (Table 2).    (N � 4), all of them were men, with a median age of 72 (IQR 70, 76) and a median Charlson comorbidity index of 4.5. 1/4 (25%) had corticoid treatment, and 3/4 were treated with high-dose heparin when bleeding was diagnosed. 2/4 (50%) had hemorrhagic shock and needed ICU admission, without any death.

Discussion
In this series of 20 cases of spontaneous hematomas in COVID-19 patients, major bleeding was both a quantitatively relevant and clinically severe complication (8.1 per 1000 COVID-19 admissions, with high direct and indirect mortality (45%)). Te incidence was signifcantly higher in patients with COVID-19 compared to those without. Te diagnosis was confrmed using CTA, and all patients underwent embolization.
Te prevalence of severe spontaneous hemorrhage in hospitalized patients with COVID-19 is not well described in the medical literature. Sposato et al. [11] showed a prevalence of 1.3%, whereas Mahmoudabadi et al. [14] reported that 0.4% of hospitalized patients with COVID-19 developed a rectus sheath hematoma. In our study, the prevalence of spontaneous hematoma was 0.8%, the midpoint between these other two studies.
Te patient profle in our series was characterized by having a high number of comorbidities and being under treatment with a therapeutic dose of anticoagulants due to   the diagnosis or suspicion of pulmonary embolism or atrial fbrillation, which is consistent with previous reports [5-8, 11, 14, 15]. Another important risk factor related to spontaneous bleeding was cough, a common sign in these patients before the event. In some studies, bleeding has also been reported to be more common in elderly patients [15]. In our case, 15% were over 80 years of age. Hypotension, with or without hypovolemic shock, was a common clinical situation in these patients, and acute anemia was a typical fnding in the blood tests [5-8, 11, 14, 15]. Regarding the respiratory status, most of the patients that bled had a moderate-to-severe COVID-19 presentation (60% with more than 50% opacities in X-ray and up to 70% with highfow oxygen therapy need), in contrast with the general nonbleeding COVID-19 cohort (24.9% and 19.1% respectively), which could infuence the higher corticosteroids dose found in the bleeding cohort (85% vs. 30.3%). Tis leads us to think about giving special importance to risk assessment and early signs of bleeding in this kind of patient and carrying out an adapted management in COVID-19 protocols, which until now more focused on prothrombotic risk (for instance, early surveillance of wall hematomas, detection of added bleeding factors, and an early CTA scan in those with hemorrhagic shock or acute abdominal pain). Te most common sites of bleeding reported in the literature are the rectus sheath, iliopsoas compartment, and retroperitoneal space [5-8, 11, 14, 15], in keeping with our results. Given the severity of this entity, even with prompt suspicion, diagnosis, and appropriate management with supportive treatment (including fuids and blood transfusion), endovascular treatment for transarterial embolization at the origin was necessary in all our cases. Tis is also common in most patients described in the literature [5-8, 12, 15].
Te mortality in our study was slightly under 50%, while in other studies it has surpassed the 50% mark [5,6,8,14,15]. Our results may be explained by the effectiveness of the endovascular treatment as a life-saving procedure. In general, the mortality described in COVID-19 patients is higher than in those without COVID-19, which is about 25% [12]. Tis could be related to the pathophysiology of COVID-19 or the associated severe respiratory insufciency [5,6,15].
We have tried to identify the risk factors associated with worse outcomes in patients with spontaneous hematoma in order to contribute to earlier detection and optimal management. However, none of the factors analyzed were signifcantly associated with increased mortality, including age, comorbidities, or persistent cough-all well-known risk factors for spontaneous hematoma [5,15]. Regarding analytical data, some research evidence supports the involvement of infammation markers like fbrinogen in bleeding severity, as a decline in fbrinogen and D-dimers concentration has been described between the second and third weeks and an average of 4 days before bleeding starts [3,4]. We did not observe diferences in laboratory data, although the median interval from initial COVID-19 symptoms to bleeding (17 days) fell within the range described. A rigorous systematic review and meta-analysis could probably resolve the uncertainties about these variables as risk factors for an unfavorable outcome. Te strengths of this study include the high number of cases and the standardized treatment protocol. However, there are also some limitations. Firstly, electronic medical records were evaluated retrospectively, which may have resulted in an information bias (a large number of laboratory variables were missing, which could have infuenced our results). Secondly, this is a single-center study, so caution is warranted when extrapolating results to other healthcare settings. Tirdly, the pathological correlation with imaging

Conclusion
Although severe bleeding is an uncommon complication in patients with COVID-19, it is more frequent than in patients with other conditions. Moreover, patients hospitalized for COVID-19 frequently take anticoagulants that could make bleeding easier, and they may have other risk factors that increase the risk of hemorrhage, although a bivariable logistic regression did not reveal any that were predictors of mortality. Embolization techniques are usually needed, but even with efective treatment, spontaneous hematomas entail a high risk of death.

Data Availability
Te dataset used to support the fndings of this study are restricted by the Hospital de Alicante ethics committee (EXP. 20014) in order to protect patient privacity. Data are available from J.M. Ramos-Rincon (jose.ramosr@umh.es) for researchers who meet the criteria for access to confdential data.

Additional Points
(i) Major bleeding in COVID-19 is an uncommon complication, but more frequent than in patients admitted with other conditions. (ii) Patients had a high rate of therapeutic anticoagulation and comorbidities. (iii) Te fatality rate was around 50% and embolization was usually required. (iv) When comparing conditions associated with death with bivariable logistic regression, we did not identify risk factors associated with an increased risk of death. (v) Further analysis is required to identify risk mortality factors in order to prevent bleeding.

Disclosure
Silvia Otero-Rodriguez and Cristina Guillen share the frst authorship

Conflicts of Interest
Te authors declare that there are no conficts of interest.